Interactions between the human genome and the environment have shaped the evolution of complex human phenotypes. Since the emergence of the genus Homo, there have been many significant changes in the interactions of humans and their ancestors with their environments. One such interaction involves dramatic increases in meat consumption prior to migrations of modern humans out of Africa. We hypothesize that humans and their ancestors have undergone selection in lipid metabolism genes in response to dietary shifts. Based on the known physiological importance of these pathways, these selective changes could strongly influence complex human phenotypes involving the nervous and cardiovascular systems and the liver. In this proposal, we will take comparative and functional genomics approaches to identify specific lipid metabolism genes and pathways undergoing selection in the human lineage. Here, we will compare and contrast quantitative differences in peroxisomal lipid metabolism in humans and closely related primate species that are primarily fruiteating, leaf-eating, grass-eating, or omnivorous. We will examine cellular differences in these metabolic pathways using fibroblasts, an established model system for peroxisomal lipid metabolism. In Specific Aim 1, we will take biochemical approaches to quantify the activities of these metabolic pathways in each species. We will focus on the catabolism of fatty acids abundant in meat-eating diets which we predict will show species-specific activities dependent upon diet. In Specific Aim 2, we will take cellular biology approaches to evaluate peroxisomal assembly and integrity in each species and correlate with their rates of lipid catabolism. In Specific Aim 3, we will take genomics approaches to evaluate the expression of peroxisomal genes and transcriptional responses to treatment with dietary lipids. In Specific Aim 4, we will take statistical genetics approaches to conduct detailed tests for selection in peroxisomal lipid metabolic genes in human and other primates. We will screen for selective sweeps that occurred prior to the migration of humans out of Africa that could mark the fixation of advantageous alleles in humans. Overall, we will conduct a detailed analysis of selective changes in human peroxisomal lipid metabolism using a variety of newly developed functional and comparative genomic approaches that could be applied towards other studies examining metabolic pathways relevant to human health and disease.